1. Institut für Pharmakologie und Toxikologie, Versbacher Strasse 9, D-97078 Würzburg, Germany

Correspondence to: Ursula Quitterer Email: toph029@rzbox.uni-wuerzburg.de

Abstract

Feedback inhibition is a fundamental principle in signal transduction allowing rapid adaptation to different stimuli. In mammalian cells, the major feedback inhibitor for G-protein-coupled receptors (GPCR) is G-protein-coupled receptor kinase 2 (GRK-2), which phosphorylates activated receptors, uncouples them from G proteins and initiates their internalization^{1, 2}. The functions of GRK-2 are indispensable and need to be tightly controlled³. Dysregulation promotes disorders such as hypertension⁴ or heart failure⁵. In our search for a control mechanism for this vital kinase, here we show that the Raf kinase inhibitor protein^{6, 7, 8} (RKIP) is a physiological inhibitor of GRK-2. After stimulation of GPCR, RKIP dissociates from its known target, Raf-1 (refs 6–8), to associate with GRK-2 and block its activity. This switch is triggered by protein kinase C (PKC)-dependent phosphorylation of the RKIP on serine 153. The data delineate a new principle in signal transduction: by activating PKC, the incoming receptor signal is enhanced both by removing an inhibitor from Raf-1 and by blocking receptor internalization. A physiological role for this mechanism is shown in cardiomyocytes in which the downregulation of RKIP restrains -adrenergic signalling and contractile activity.